Systemic Lupus Erythematosus (SLE) is inherited as a complex polygenic trait, which is further complicated by genetic and phenotypic heterogeneity. To define the genetics of this disease, the investigators and others have taken advantage of the uniform genetic composition of inbred mouse strains, of which several spontaneously develop clinical and immunopathologic characteristics similar to human SLE. They have previously identified the chromosomal locations of autoimmune susceptibility loci for the four main lupus strains that include the NZB, NZW, BXSB, and MRL-Faslpr mice. These studies demonstrated a multiplicative threshold inheritance of disease traits with specific combinations of loci contributing to each immunopathologic stage. Among the loci identified, four (Lmb1 to 4) from the MRL-Faslpr x C57BL/6-Faslpr cross were significantly linked to diseased traits with the highest likelihoods. Further mapping studies have revealed additional Lmb loci linked to the production of specific autoantibodies. Reciprocal interval congenic lines for all four Lmb loci were subsequently generated and significant component phenotypes were found for Lmb3 (chromosome 7) and to a lesser extent Lmb11 (chromosome 4). This proposal will extend this work by more precisely mapping Lmb3 and cloning the specific underlying genetic alterations. Cell transfer studies will be performed to determine whether expression of Lmb3 in bone marrow cells, T lymphocytes and/or B cells is necessary for the development of autoimmunity. To define the interactions of the Lmb loci, additional derivative congenic mice with combinations of one to four Lmb loci will be generated and analyzed. Finally, further characterization of the Lmb1 congenic mice and fine mapping of the Lmb1 locus will be performed. These studies should yield significant new insights into the etiopathogenesis of systemic autoimmunity, and may lead to new diagnostic and therapeutic approaches for human SLE.